Atherosclerosis and thrombosis are the major causes of death in Western civilization. They are complex syndromes with numerous environmental and inherited risk factors which interact in ways that are poorly understood. Elevated blood levels of homocysteine and the lipoprotein Lp(a) have both been shown to be independent risk factors for vascular disease. There is recent in vitro evidence to suggest that homocysteine and Lp(a) may act in ways which potentiate their delerious activity. Exploration of this interaction could lead to means to recognize and prevent the consequences of moderate or severe elevation in these risk factors. Homocysteine has been shown to increase the affinity of binding of Lp(a) to fibrin. Fibrin binding, and the subsequent inhibition of plasminogen activation and clot lysis are key pathogenic activities of Lp(a), contributing to atherosclerosis, cerebrovascular stroke and other vascular abnormalities. The investigators propose examine the nature of the homocysteine/Lp(a) fibrin interaction in vitro and in human plasma using biochemical and biophysical techniques, with wild type and mutated forms of Lp(a). Genetically manipulated mouse strains provide an animal model system in which to rigorously test this interaction in vivo. The applicants will use apo(a) transgenic mice and cystathionine Beta-synthase deficient mice to create a manipulatable, small animal model of elevated homocysteine and Lp(a). The mice will be utilized in several assays of atherosclerosis and thrombosis, to test hopotheses concerning their synergistic pathological interactions which include the ability of homocysteine to modulate fibrin binding of Lp(a), interfere with clot lysis, and drive atherogenesis by altering growth factor activation in the vessel wall. The interaction of homocysteine and Lp(a) will also be explored in the settings of induced systemic thrombosis and of venous clot lysis. Finally, these animal models will be utilized to test the efficacy of drugs designed to reduce the concentration of homocysteine, alter the activity of Lp(a), improve endothelial function, or otherwise modulate pathogenic events triggered by these two important risk factors for cardiovascular disease. (End of Abstract)